Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells

Cell Stem Cell. 2020 Aug 14;S1934-5909(20)30359-3. doi: 10.1016/j.stem.2020.07.021. | PubMed

Courtney L Jones¹, Brett M Stevens², Daniel A Pollyea², Rachel Culp-Hill³, Julie A Reisz³, Travis Nemkov³, Sarah Gehrke³, Fabia Gamboni³, Anna Krug², Amanda Winters², Shanshan Pei², Annika Gustafson², Haobin Ye², Anagha Inguva², Maria Amaya², Mohammad Minhajuddin², Diana Abbott⁴, Michael W Becker⁵, James DeGregori⁶, Clayton A Smith², Angelo D'Alessandro⁶, Craig T Jordan⁷

1. Division of Hematology, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address: courtney.jones@uhnresearch.ca.
2. Division of Hematology, University of Colorado Denver, Aurora, CO 80045, USA.
3. Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, USA.
4. Department of Biostatistics and Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
5. Department of Medicine, Division of Hematology/Oncology, University of Rochester, Rochester, NY 14627, USA.
6. Division of Hematology, University of Colorado Denver, Aurora, CO 80045, USA; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, USA.
7. Division of Hematology, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address: craig.jordan@ucdenver.edu.

Abstract

We previously demonstrated that leukemia stem cells (LSCs) in de novo acute myeloid leukemia (AML) patients are selectively reliant on amino acid metabolism and that treatment with the combination of venetoclax and azacitidine (ven/aza) inhibits amino acid metabolism, leading to cell death. In contrast, ven/aza fails to eradicate LSCs in relapsed/refractory (R/R) patients, suggesting altered metabolic properties. Detailed metabolomic analysis revealed elevated nicotinamide metabolism in relapsed LSCs, which activates both amino acid metabolism and fatty acid oxidation to drive OXPHOS, thereby providing a means for LSCs to circumvent the cytotoxic effects of ven/aza therapy. Genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide metabolism, demonstrated selective eradication of R/R LSCs while sparing normal hematopoietic stem/progenitor cells. Altogether, these findings demonstrate that elevated nicotinamide metabolism is both the mechanistic basis for ven/aza resistance and a metabolic vulnerability of R/R LSCs.

Presented By Courtney Jones